Hypertension is a major health problem in the United States that ultimately affects about one quarter of the population and contributes to heart attacks, stroke, and kidney failure. Available evidence suggests that a major mechanism for the regulation of arterial blood pressure resides in the ability of the kidneys to control extracellular fluid volume by alterations in the excretion of salt and water. Thus, the transporters that mediate sodium reabsorption across the apical membranes of renal epithelial cells, some of which serve as targets for antihypertensive medications, are likely to serve as integral components of the renal systems mediating control of arterial blood pressure. To test this hypothesis we propose to develop and analyze mouse models in which the genes encoding these transporters are ablated. In aim 1 we will use gene targeting technology to develop mice with disruptions of the genes encoding the apical Na/H exchanger of the proximal tubule, the Na,K,2C1cotransporter of the thick ascending limb of Henle, the NaC1 cotransporter of the distal convoluted tubule, and the Na channel of the collecting duct. The viability of mutant offspring will be assessed by analysis of genotype frequency, embryonic/fetal development, birthweight, survival and growth rate, and tissue histology, thereby allowing a determination of whether each transporter is essential for survival or, alternatively, whether there are compensatory mechanisms that overcome the loss of a particular transporter. In aim 2 we will determine whether these primary genetic defects, in which one or both copies of the genes encoding each of the apical sodium transporters has been disrupted, are capable of producing a chronic alteration in arterial blood pressure. By utilizing these genetically altered animals, in which sodium reabsorption in individual nephron segments has been perturbed, it will be possible to assess the relative importance of each transporter and nephron segment in the control of arterial blood pressure, as well as some of the renal compensatory mechanisms. Wild-type and mutant animals will be maintained on low, normal, and high sodium diets, and chronic.alterations in blood pressure will be analyzed by both femoral artery catheterization and tail cuff procedures. Alterations in glomerular filtration rate, renal plasma flow, plasma volume, urinary excretion of Na+ and K+, plasma levels of renin and aldosterone, and Na,K-ATPase activity along the nephron will be assessed, and morphological correlates of compensatory changes will be analyzed by electron microscopy. We anticipate that the mice developed in this proposal will become valuable and widely used models for detailed analysis of the mechanisms underlying the relationship between renal Na+ handling and arterial blood pressure.